ABSTRACT Despite decades of research, the immunological correlates of protection against HIV-1 infection in humans or SIV infection in nonhuman primates remain poorly understood. In contrast, studies on Friend retrovirus (FV) infection in mice highlighted the importance of the neutralizing antibody response in disease recovery and vaccine protection, a response widely considered as critical for a successful HIV-1 vaccine. Interestingly, the neutralizing antibody response in FV infection is significantly influenced by a key host gene, Rfv3. We recently identified Rfv3 as Apobec3, a potent innate restriction factor that counteracts a broad range of retroviruses including HIV-1 (Santiago ML et al. 2008. Science 321: 1343-6). This discovery revealed an unexpected link between the innate and humoral arms of the immune response that may have important implications for HIV-1 vaccine development. Our overall objective in this proposal is to probe the fascinating link between Apobec3 activity and the neutralizing antibody response against pathogenic retroviral infections in three species: mice, monkeys and humans. In Specific Aim 1, the underlying mechanism of the Apobec3/Rfv3 phenotype will be dissected in the FV murine model. This will involve in-depth studies on virus dynamics, interferon regulation and pathology in wild type versus Apobec3-deficient mice, and a detailed characterization of neutralizing antibodies against the FV envelope protein. Since the simian and human homologues of Apobec3 are thwarted by the lentiviral Vif protein, we hypothesize that attenuating Vif function may rescue Apobec3 and improve neutralizing antibody responses. In Specific Aim 2, wild type and Vif-attenuated SIV and SHIV strains will be used to infect rhesus macaques. Apobec3 function and neutralizing antibody kinetics, potency, breadth and epitope specificity will be monitored from sequential blood samples. Finally, Apobec3 function has been linked to HIV-1 resistance, but its impact on HIV-1 antibody responses remains unknown. The recent acquisition of samples from the earliest stages of HIV-1 infection therefore opens an unprecedented opportunity to link innate Apobec3 function and neutralizing antibody development. Thus, in Specific Aim 3, we propose to examine the relationship between Vif functional diversity, Apobec3 inducibility, interferon regulation, and envelope-directed antibody development in HIV-1 infection. We have assembled a highly qualified team of investigators with expertise in Apobec3/Vif biology, murine retrovirus immunology, the SIV and SHIV macaque model systems, and HIV-1 pathogenesis for this project. We postulate that understanding Apobec3-mediated innate immunity may yield promising and "outside the box" insights for augmenting neutralizing antibody responses against HIV-1 infection.